The present invention relates to the prevention and treatment of eye diseases or disorders. More particularly, this invention relates to compositions and methods for arresting oxidation processes damaging to the eye.
It is known that oxygen-derived radical species are important mediators of several forms of tissue damage, such as ischemic and traumatic injuries to organs and tissues, inflammatory responses, and injuries which result from the intra-cellular metabolism of chemicals and drugs. In particular, oxygen-derived radical species have been suggested as destructive forces in such maladies as head and spinal cord injury, stroke, shock, Parkinsonism, muscular dystrophy, emphysema, ARDS (acute respiratory distress syndrome), asthma, aging, post-myocardial infarct tissue destruction, drug toxicity, radiation damage, transplant rejection, and burn damage.
The reduction of oxygen occurs in several stages which progressively include the super-oxide anion, hydrogen peroxide, hydroxyl radical, and finally water. Various biological processes can generate these species from oxygen or oxygen-derived materials. For example, phagocytosis, cytochrome P450 metabolic pathways, the biosynthesis of prostaglandins and leukotrienes, xanthine/xanthine oxidase, mitochondrial electron transport, and lipid peroxidation can all generate reactive oxygen species.
One target for damage by oxygen-derived radical species is the cell membrane. Oxidative damage at the cell membrane is enhanced by lipid peroxidation which is a chain reaction that alters or destroys the polyunsaturated fatty acids of the membrane phospholipids. Membrane bound proteins are also affected. The structural integrity and the function of cell membranes are irreversibly changed. Extra-cellular calcium can enter the cell, and calcium-dependent phospholipases and protein kinases are activated. These phospholipases, once activated, will cleave fatty acids from phospholipids and cause additional change in the chemical composition and physiologic state of the cell membrane. The free fatty acids are converted by cyclooxygenases to prostaglandins and thromboxanes. Inflammatory agents like a variety of HETES are also generated by lipoxygenases. In addition, new radical species are formed during the cascade. Radical attack by hydrogen peroxide of unsaturated fatty acids may be catalyzed by iron near or within the cell membrane. Iron can convert lipid hydroperoxides to peroxy and alkoxy radicals. It can interact with molecular oxygen or reduced oxygen radical species.
Lipid peroxidation normally proceeds as a radical driven chain reaction involving oxygen where the lipid peroxyl radical (LOO.) formed through initiation (reactions 1 and 2) attacks a second unsaturated fatty acid (reaction 3). ##STR1## .alpha.-Tocopherol (Vitamin E) inhibits lipid peroxidation by scavenging LOO. (reaction 4), preventing lipid radical chain reactions from occurring, and is itself converted into a radical EQU LOO.+.alpha.TC.fwdarw.LOOH+.alpha.TC. [4].
The .alpha.TC radical then decomposes to tocopherolquinone and other products and thus, effectively terminates the chain reaction.
In addition to their adverse effects on various body tissues (e.g., as described above), oxidation reactions can also cause damage to the eye. It is known, for example, that the aqueous humor of the eye is rich in hydrogen peroxide and that the anterior tissues bathed by the aqueous humor exist in an extraordinarily oxidative environment. It is further known that prolonged exposure of the eye to light of certain wavelengths can cause harm to anterior, posterior and other tissues of the eye. Indeed, prolonged exposure to light produces oxidative damage in many tissues such as the lens, retina and retinal pigmented epithelium. Additionally, chronic exposure to light and to an oxidative environment is believed to induce cumulative damage, which, depending on the severity of the exposure and the susceptibilities of the individual exposed can result, in the best of cases in normal aging and discomfort and, in the worst of cases, in pathological disorders.
In addition to light exposure, such a cascade leading to the production of harmful oxidative species is initiated by inflammation, during trauma, following ischemia, during hemorrhaging, upon stimulation by a variety of drugs and endogenous cell regulators, upon pressure exertion on tissues as occurs diurnally as a result of intraocular pressure changes in the anterior chamber of the eye, and indeed to a host of processes both normal and abnormal that occur continuously in the eye. Polyunsaturated fatty acids are also readily subjected to less specific chemical (non-enzymatic) oxidation to yield hydroperoxides, hydroxy fatty acids and malondialdehyde, materials which can contribute to the overall damage that accumulates with time.
Thus, oxidative processes are now known to play a role in age-related cataracts, light-induced retinal damage, other retinopathies such as diabetic retinopathy and age-related macular degeneration, inflammatory damage (such as that seen in uveitis), vascular leakage and edema (as in cystoid macular edema), accidental or surgical trauma, angiogenesis, corneal opacities, retolental fibroplasia, and some aspects of glaucoma.
To counteract the harmful effects of the oxidative processes described above, such as free radical-mediated lipid peroxidation, the body naturally produces a number of defensive compounds such as .alpha.-tocopherol (vitamin E, which is an antioxidant), ascorbic acid, glutathione, catalase and superoxide dismutase. Thus, as set forth above, vitamin E is known to be a scavenger of both lipid peroxyl radicals and oxygen radicals, as well as to have a membrane-stabilizing action. Indeed, it is believed that chronic dietary vitamin E supplementation can attenuate postischemic cerebral hypoperusion by inhibiting the lipid peroxidative process.
A group of 21-aminosteroids have also been found to act as antioxidants, and some aminosteroids have been employed intravenously, intraperitoneally and orally in the treatment of central nervous system injury, head and spinal injury, and edema associated with acute stroke. It has been reported that intravenous administration of a citrate buffered saline solution of 0.15% by weight of U-74600F for treatment of spinal cord or brain injury has been effective to arrest lipid peroxideation therein. It is also known that in performing toxicology studies with various drugs, polysorbate 80 and hydroxypropylcellulose and the like can be used as suspending agents in low viscosity formulations.
International Publication Number WO 87/01706, which discloses a number of aminosteroids and their therapeutic use in a variety of contexts, as well as administration techniques and dosages, does not disclose treatment or prevention of ophthalmic diseases or disorders. Nor does it disclose topical application to the eye or administration by intraocular injection. Moreover, prior art formulations which cannot be comfortably and effectively applied to the eye have limited applicability.
In order to enhance the eye's ability to protect from damaging oxidative processes such as can occur with aging or due to a sudden trauma, it has been proposed to supply vitamin E to the eye by oral administration in view of its known ability to inhibit such oxidative processes. Vitamin E does scavenge free radicals and function as an antioxidant. However, it must be given chronically to have any effect. Moreover, even when administered chronically with other antioxidants, such as glutathione and vitamin C, the results are at best mixed.